Interleukin (IL)-23 was discovered by searching sequence databases with a computationally derived profil of members of the interleukin-6 helical cytokine family. This search led to the discovery of a novel cytokine subunit which was named IL-23p19 (p19) which was homologous to the IL-12p35 subunit. This IL-12p35 subunit dimerizes with IL-12p40 subunit to form IL-12. Expression of p19 with IL-12p40 led to the secretion of a heterodimeric protein which was called IL-23.
The p40 subunit of IL-23 has three domains labeled D1, D2 and D3. Each domain is a β-sheet structure with the D2 domain containing the C177 interchain disulphide bond. There is also an N-linked glycosylation site on D2.
The p19 subunit resembles IL-12p35 in that it contains a four helix bundle. However, a truncated helical length and a ‘tilt’ and ‘roll’ in IL23p19 relative to IL-12p35 results in an altered footprint. IL-23p19 also differs in the manner in which it interacts with IL-12p40 when compared to IL-12p35.
The specific effects of IL-23 on its target cell types are mediated by the IL-23R complex, which comprises IL-12β1 and IL-23R. IL-12β1 binding to IL-23 is mediated via the IL-12p40 subunit.
IL-23p19 of IL-23 is responsible for binding to IL-23R thereby conferring IL-23 selectivity on the IL-23R complex.
IL-23 is secreted by activated human macrophages as well as dendritic cells. IL-23 predominantly acts on memory T-cells and has been postulated to promote autoimmune disease through the regulation of IL-17A and IL-17F as demonstrated in the ability of murine splenocytes to secrete IL-17 in response to IL-23. In humans the IL-23/IL-17 pathway is present, and IL-23 has been shown to be a good inducer of IL-21, IL-22, IFN-γ, and TNF-α along with IL-17, all of which are pro-inflammatory cytokines. In vitro IL-6 and TGF-β1 promote the development of naïve T-cells to the TH17 T-cell pathway. These cells are further driven in an autocrine manner via secretion of IL-21. IL-23 and/or IL-1β are thought to maintain cells in this TH17 response.
Since both IL-12 and IL-23 contain a common subunit, it has been difficult to attribute disease states solely to overproduction of one interleukin or the other. However research indicates that IL-23 dysregulation has been implicated in psoriasis, Crohn's disease and multiple sclerosis, among other autoimmune diseases.
Given that IL-23 is involved in various pathological conditions, antagonists specific for this cytokine are desirable. However, specifically targeting this cytokine has proven difficult since both of the subunits of IL-23 are shared with other dimeric cytokines. For example, the IL-12p40 subunit is also a component of IL-12 and IL-23p19 is also a component of heterodimeric cytokines such as zcyto33f2 as described in U.S. Pat. No. 7,196,172.